tbuckley/cabot-search huggingface dataset:
UCLA B-13: A phase 1b trial evaluating the safety of ribociclib, tucatinib, and trastuzumab in patients with metastatic, HER2+ breast cancer and a multicenter, randomized, open-label, phase 2 study of preoperative treatment with ribociclib, trastuzumab, tucatinib, with or without fulvestrant versus docetaxel, carboplatin, trastuzumab, and pertuzumab in HR+/HR-, HER2+ breast cancer.
Authors: Nicholas Patrick McAndrew, Sara A. Hurvitz, Merry L. Tetef, Christine Kivork, Larissa Ikenouye, Dennis J. Slamon
Journal: Journal of Clinical Oncology (2023)

TPS1116 Background: Overexpression of the HER2 protein is an important prognostic and predictive biomarker in about 20% of breast cancers, and while trastuzumab-based regimens are still considered standard of care in the early and metastatic settings, these regimens require chemotherapy co-administration. Pre-clinical mouse models suggest that a tucatinib/CDK 4/6 inhibitor combination regimen may be equally effective as standard regimens. Thus, finding more effective/tolerable therapies for this disease remains an area of unmet need. This randomized, open label, phase II clinical trial will explore the safety and efficacy of two novel, chemotherapy free combination drug regimens, given neoadjuvantly, in patients with anatomic stage I-III, HER2+ breast cancer. Methods: Phase 1b dose escalation trial: To establish the safety profile of the combination of ribociclib and tucatinib, an initial dose-finding phase 1b trial will be performed in patients with metastatic HER2+ breast cancer before moving into the larger phase 2 trial. 3-6 patients will be assigned sequentially to groups of increasing doses of ribociclib (200mg-600 mg) with fixed doses of tucatinib (300mg) and trastuzumab (SOC dosing) for a total of four 28-day cycles. The recommended phase 2 dose will be established when 6 patients have been treated at the highest dose level cohort. As of January 2023, 1 participant has been enrolled in dose level 1. Phase 2 neoadjuvant trial: Following MTD determination and approval from regulatory boards and funding partners, a total of 100 patients will be enrolled in the phase 2 portion of the study. Enrollment will be stratified by hormone receptor status. Patients will be randomized 1:1 (25 in each group) to receive six cycles of one of the following regimens: ribociclib/trastuzumab/tucatinib/+/- fulvestrant (28 day cycles) or docetaxel/carboplatin/trastuzumab/pertuzumab (SOC, 21 day cycles), preceded by one run-in cycle of trastuzumab/pertuzumab. To assess for changes in predictive molecular biomarkers, biopsies pre-and-post cycle 1 will be planned in all arms. Early imaging response assessments in the experimental arms will be planned after 2 cycles. Other endpoints include safety, changes in Ki67 expression, RCBi, biomarker analysis, and health-related quality of life. Clinical trial information: NCT05319873 .
Phase I/II study of stereotactic radiosurgery with concurrent olaparib followed by adjuvant durvalumab and physician’s choice systemic therapy in patients with breast cancer brain metastases.
Authors: Colette Shen, Yara Abdou, Linda Chen, Xianming Tan, Gaorav P. Gupta, Filipa Lynce, Mina Lobbous, Erica Michelle Stringer-Reasor, Carey K. Anders
Journal: Journal of Clinical Oncology (2023)

TPS1133 Background: Despite progress in the treatment of brain metastasis for HER2+ breast cancer, outcomes for patients with HER2-negative breast cancer brain metastases remain poor. Current standard of care consists of local therapies, including surgery and radiotherapy, followed by systemic therapy. Preclinical studies show inhibitors of poly(ADP-ribose) polymerase (PARP) are effective in combination with radiation therapy as a DNA damage response inhibitor. Triple-negative breast cancer (TNBC) has higher rates of homologous recombination deficiency compared to other breast cancer subtypes, and together with HER2-negative, BRCA-mutated breast cancer would be particularly sensitive to PARP inhibition. PARP inhibition has also demonstrated promising efficacy combined with immunotherapy in patients with germline BRCA-mutant and metastatic TNBC in clinical trials (MEDIOLA, TOPACIO). In addition, immunotherapy with stereotactic radiosurgery (SRS) is associated with favorable intracranial control and survival in patients with brain metastases. We hypothesize that this biologically-driven combination will enhance local control of SRS-treated brain metastases through synergy with PARP inhibition, while controlling micrometastatic disease in the brain and extracranial sites via potentiation of the immune response. Methods: We are conducting a multi-institution, Phase I/II trial of SRS plus olaparib, followed by durvalumab (with physician’s choice systemic therapy), for patients with TNBC (any BRCA status) or HER2-negative with BRCA-mutated (germline or somatic) breast cancer brain metastases [NCT04711824]. A total of 41 patients are planned for enrollment at 8 sites. The primary objectives are to evaluate safety and tolerability (Phase I) and determine intracranial disease control at 6 months (Phase II) of this treatment combination. Secondary objectives include determining clinical activity via intracranial and global progression-free survival, overall survival, and intracranial and extracranial response rate. Exploratory objectives will assess potential biomarkers of treatment response, including changes in circulating tumor cells and DNA in blood and cerebrospinal fluid, germline and tumor mutations in DNA repair pathway genes, and PD-L1 expression, as well as quality of life and patient-reported outcomes. A surgical sub-study (n=5) will evaluate olaparib concentration/distribution in resected brain metastases. As of January 2023, cohort 1 of phase I has been completed without dose-limiting toxicity. Clinical trial information: NCT04711824 .
Use of PLR and NLR to evaluate the efficacy and prognosis of neoadjuvant chemotherapy with lobaplatin in triple-negative breast cancer.
Authors: Cheng Wang, Qiyun Shi, Guozhi Zhang, Wenting Yan, Xiujuan Wu, Andi Wan, Siyi Xiong, Long Yuan, Hao Tian, Dandan Ma, Jun Jiang, Yi Zhang, Xiaowei Qi
Journal: Journal of Clinical Oncology (2023)

594 Background: Previously, we showed that addition of lobaplatin (L) to taxane (T) combined with anthracycline (E) could improve the pathological complete response (pCR) rate of neoadjuvant therapy for triple-negative breast cancer (TNBC) and lengthen long-term survival significantly, but the therapeutic markers of this regimen are not known. We investigated if the platelet/lymphocyte ratio (PLR) and neutrophil/lymphocyte ratio (NLR) could be used to predict the efficacy of the TEL regimen. Methods: Eighty-three patients with TNBC (stage I–III) who received TEL (docetaxel (T) at 75 mg/m 2 , epirubicin (E) at 80 mg/m 2 , and lobaplatin (L) at 30 mg/m 2 ) from January 2014 to August 2019 were recruited. They received four cycles before surgery and two cycles after surgery. Patients were divided into four groups according to the mean values of the PLR (145.71) and NLR (2.74): high PLR (PLR+), low PLR (PLR−), high NLR (NLR+), and low NLR (NLR−). Differences in the total pathologic complete response (tpCR) rate, event-free survival (EFS), and overall survival (OS) were analyzed in different groups of patients using the TEL protocol. Results: The tpCR rate in the PLR− group was 49.0% (25/51), which was significantly higher than that in the PLR+ group (25.0% (8/32); odds ratio (OR) = 2.885, 95% confidence interval (CI) = 1.093–7.612, P = 0.032). The tpCR rate in the NLR− group was 49.1% (26/53), which was significantly higher than that in the NLR+ group (23.3% (7/30); OR = 3.164, 95% CI = 1.161–8.626, P = 0.024). The tpCR rate of the PLR−NLR− group was 53.7% (22/41), which was significantly higher than that of the PLR+/NLR+ group (26.1% (11/42), with a high proportion of any index (OR = 3.263, 95% CI = 1.298–8.204, P = 0.012). The median duration of follow-up was 69 months. EFS and OS in the NLR− group were significantly longer than those in the NLR+ group (hazard ratio (HR) = 5.946, 95% CI = 1.526–23.169, P = 0.010 for EFS; HR = 7.803, 95% CI = 1.565–38.907, P = 0.012 for OS). Five-year EFS was 95.1% for the PLR−NLR− group, 91.0% for the PLR+NLR− group, 76.0 for the PLR+NLR+ group, and 59.1% for the PLR−NLR+ group. Compared with the PLR+/NLR+ group, patients in the PLR-NLR- group had the longest EFS (P = 0.002). Conclusions: PLR and NLR could be used to predict the efficacy of neoadjuvant therapy with taxane, anthracycline, and lobaplatin regimen in TNBC, and the low-proportion group had a higher tpCR rate and a better long-term prognosis. Clinical trial information: ChiCTR-TRC-14005019 .
A phase II single-arm, open-label trial of T-DM1 (ado-trastuzumab emtansine) and neratinib for HER2-positive breast cancer with molecular residual disease (KAN-HER2 MRD).
Authors: Mitchell Elliott, Jesús Fuentes Antrás, Philippe Echelard, Nicholas Meti, Alisa Nguyen, Michelle Liu, Carolina Sanabria Salas, Christopher Gareth Smith, Moira Katherine Rushton, Lillian L. Siu, Hal K. Berman, Philippe L. Bedard, David W. Cescon
Journal: Journal of Clinical Oncology (2023)

TPS620 Background: HER2-positive breast cancer is a biologically and clinically aggressive subtype that has historically been associated with poor outcomes, but for which there are now multiple effective targeted therapies. Patients who have residual disease following standard neoadjuvant therapy have an elevated risk of metastatic recurrence. In addition, the detection of circulating tumor DNA (ctDNA) in the adjuvant period is strongly associated with relapse and can further stratify patients with residual disease. The ctDNA-based detection of molecular residual disease (MRD) is an emerging strategy to identify patients for treatment intensification, and may enable the development of novel curative treatment strategies for “recurrence interception”. Preclinical and clinical evidence support the investigation of neratinib, an irreversible inhibitor of the HER2 tyrosine kinase, in combination with standard T-DM1 in the adjuvant setting for patients with HER2-positive breast cancer and evidence of MRD. Methods: KAN-HER2 MRD is a multicentre, investigator-initiated, open label, single arm phase II trial to evaluate the addition of neratinib to standard T-DM1 in patients with detected MRD. Participants with HER2-positive breast cancer and residual disease following neoadjuvant therapy are pre-screened (Part A) for MRD using a tumor-informed assay (NeoGenomics RaDaR). Those with ctDNA detected following 2-6 cycles of adjuvant T-DM1 will proceed to the interventional phase (Part B) where neratinib is added to standard T-DM1 at the previously-determined recommended phase 2 combination dose of 160 mg/day, in continuous cycles. The primary endpoint is the rate of ctDNA clearance at 12 weeks after treatment initiation (ctDNAwk12); the study is designed with a 2-stage approach and has sufficient power to detect a clearance rate of 40%. Secondary endpoints include MRD rates and their clinical correlates, invasive disease free survival (iDFS), and safety. Bio-specimens including diagnostic biopsies, residual disease, and peripheral blood are being collected from all participants for additional correlative studies. Enrolment in Part A was initiated at the first trial site (Princess Margaret Cancer Centre) in December 2022. KAN-HER2 represents the first reported MRD-directed interception trial for HER2-positive breast cancer. Clinical trial information: NCT05388149 .
Association of state policies regulating short-term limited-duration insurance plans and cancer stage at diagnosis.
Authors: Justin Michael Barnes, Anne C. Kirchhoff, Robin Yabroff, Fumiko Chino
Journal: Journal of Clinical Oncology (2023)

1589 Background: In 2018, federal regulations expanded access to short-term limited duration insurance (STLD) plans. STLD plans generally limit coverage of medical services and have no cost-sharing caps, which can delay a cancer diagnosis. Furthermore, uptake of STLD plans can destabilize individual insurance markets, leading to increased prices and subsequent barriers to care for comprehensive insurance plan enrollees. Several states introduced legislation prohibiting and/or limiting STLD plans, but it is unclear whether STLD plans or policies restricting their proliferation have affected cancer stage at diagnosis. Methods: Individuals ages 18-64 years with staged first primary malignancies diagnosed 2016-2019 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Difference-in-differences (DID) analyses evaluated changes in early-stage (stages 0 [breast and bladder only] through II) diagnoses from pre- (2016-2017) to post- STLD expansion (2019; 2018 was excluded as washout/phase-in period) between states with policies prohibiting and/or limiting STLD plans vs. states with no policies regulating STLD plans. In some states limiting but not prohibiting STLD plans, insurers stopped selling STLD plans; we conducted additional analyses by state STLD plan availability in 2019. Linear probability models utilized cluster-robust standard errors (clustered at state level) and adjusted for fixed state and year effects, sociodemographic covariates, and cancer site. Sensitivity analyses excluded states that expanded and/or substantially changed Medicaid eligibility during the study period. The plausibility of the parallel trends assumption was tested in adjusted models restricted to the pre-policy period (2016-2017) and was satisfied for all analyses. Results: 398,190 individuals were included. In adjusted DID analyses, early-stage diagnoses increased 0.95 percentage points (95% CI = 0.53 to 1.38, p&lt;.001) in states that prohibited vs. did not regulate STLD plans, but there was no relative change in early-stage diagnoses in states with other policies limiting STLD plans (p=.25). Relative to states where STLD plans remained available, there was a nonsignificant increase in early-stage diagnoses in states where legislation stopped the sale of STLD plans, with greater evidence for an increase after excluding states with Medicaid eligibility changes (1.03, 95% CI = 0.71 to 1.35, p&lt;.001). There were no differential changes in early-stage diagnoses by state group in falsification tests limited to individuals &gt;65 years-old, who were Medicare-age-eligible. Conclusions: State legislation prohibiting and/or leading to the cessation of STLD plans was associated with an increased rate of early-stage cancer diagnoses. Alternatively, the proliferation of STLD plans was associated with a differential decreased rate of early-stage cancers.
HER2 persistence after treatment with T-DXd in breast and gastrointestinal cancers.
Authors: Joshua Z. Drago, Fresia Pareja, Komal L. Jhaveri, Elaine M. Walsh, Geoffrey Yuyat Ku, Steven Brad Maron, Yelena Y. Janjigian, Mark E. Robson, Jorge S. Reis-Filho, Shanu Modi, Pedram Razavi, Sarat Chandarlapaty
Journal: Journal of Clinical Oncology (2023)

1052 Background: T-DXd is a HER2-targeted antibody drug conjugate approved for treatment of advanced HER2-positive breast and gastroesophageal cancers and HER2-low breast cancers. The prevalence of HER2 loss after exposure to T-DXd is unknown and has implications for treatment strategies in refractory patients. Methods: We investigated clinically reported HER2 immunohistochemistry (IHC) scoring on post-treatment tissue biopsies from patients who received at least 2 cycles of T-DXd as of 2/2023. IHC was performed using mAB clone 4B5 (Ventana) and scored by ASCO/CAP guidelines on a scale of 0 to 3+. MSK-IMPACT next generation sequencing (NGS) was performed on paired pre- and post-treatment samples when available. Statistics are descriptive. Results: A total of 62 patients with breast, gastroesophageal, or colon cancer had available post-treatment biopsies. The majority (n = 51) had breast cancer, including 32 with HER2-positive and 19 with HER2-low disease. Median time on therapy was 30 weeks in HER2-positive and 21 weeks in HER2-low breast cancer. All 32 patients with HER2-positive breast cancer had detectable HER2 expression by IHC on post-treatment biopsies (median IHC score 2+; range 1+ to 3+). Of those with HER2-low breast cancer, 12 (63.1%) patients had detectible IHC after treatment. Of the 7 with IHC scores of zero, 3 also had scores of zero on the most proximal pre-treatment biopsies. Seven patients with gastroesophageal and 3 with colorectal cancer were included, with a median time on therapy of 12 and 9 weeks respectively, of which 1 (9%) exhibited HER2-loss after treatment. Among all patients with HER2-positive cancers, the rate of complete HER2-loss by IHC after exposure to T-DXd was 2.3%. Thirty-two patients had paired genomic analysis, including 25 breast and 7 gastrointestinal cancers. No change was observed in the fraction of genome altered (p = 0.0736, q = .327) or tumor mutational burden (p = 0.139, q = .487) with T-DXd exposure. Changes in ERBB2 copy number did not show clear directionality, with 15 patients (46.7%) exhibiting ERBB2 amplification pre-treatment and 12 (37.5%) post-treatment, the sum of 3 temporal gains and 6 losses of ERBB2 amplification across the threshold of 1.8. Conclusions: HER2 remained detectable by IHC in the majority of patients treated with T-DXd in this cohort, especially those with HER2-positive cancers. These findings suggest that resistance to T-DXd may occur via target-independent factors, and that HER2 could still be exploited therapeutically in these populations. Further prospective studies using quantitative assays are needed to confirm these hypotheses. [Table: see text]
Clinical characteristics and outcome of <i>PIK3CA</i> mutated hormone receptor positive (HR+), human epidermal growth factor 2 negative (HER2-), advanced breast cancer (BC) treated with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i): Real world data.
Authors: Natalija Dedic Plavetic, Katarina Čular, Marija Križić, Marina Popovic, Stjepko Plestina, Tajana Silovski
Journal: Journal of Clinical Oncology (2023)

e13078 Background: BC is the most common malignant disease and leading cancer-related cause of death in women. Despite significant achievements in the treatment, advanced BC (aBC) is still an incurable disease. HR+/HER2- subtype accounts for 70% of all BC. One of the most common mutations in BC is the PIK3CA gene mutation which can induce endocrine and chemo- resistance. In early BC, patients (pts) with PIK3CA mutations mostly have better, but in aBC worse prognosis. Standard first-line treatment for HR+/HER2- aBC is a combination of CDK4/6i and endocrine therapy. PIK3CA status is most often assessed in this group of pts and combination of alpelisib - PIK3CA inhibitor and fulvestrant is second-line treatment option in PIK3CA mutated pts. Methods: Medical records of HR+/HER2- aBC pts who started CDK4/6i therapy between 01.08.2018. and 01.10.2020. were analyzed with prior University Hospital Center Zagreb Ethics Committee approval. Demographics, tumor characteristics, clinical presentation and therapy information were collected. Molecular analysis of PIK3CA mutations was performed on tumor tissue samples. Time to treatment failure (TTF) was analyzed using the Kaplan-Meier method and the data cut-off was 31.12.2022. Results: Of the 103 pts with determined PIK3CA status, 45 (43.7%) had a detectable mutation. Median follow-up was 35 months. CDK4/6i were first line therapy in 31 (68.9%) pts with and 29 (50%) pts without PIK3CA mutation. Endocrine resistance, de novo metastatic disease and bone marrow infiltration were more common in PIK3CA mutated subgroup. The incidence of visceral metastases was similar in both groups, whereas liver metastases were more common in the unmutated group. Disease progression was observed in 69 (67%) pts, 28 (40.6%) of whom were PIK3CA mutated. Median TTF in mutated subgroup was 24 months (95% CI 21-33) and 25 months in unmutated subgroup (95% CI 19-36). During the follow-up period, 35 (34%) pts died, 14 (40%) of whom were PIK3CA mutated. Odds ratios in pts with a PIK3CA mutation. Conclusions: There was no relevant difference in TTF between two groups. However, PIK3CA mutated subgroup had more aggressive clinical features - more often presented with bone marrow infiltration and de novo aBC, statistically relevant OR 5.158 and 2.323 respectively, which is related to lower quality of life and highlights the importance of treatment improvement for this subgroup of pts. [Table: see text]
HER2-low status discordance between primary and recurrent/metastatic breast cancer in a large-scale cohort.
Authors: Mingxi Lin, Ting Luo, Hui Zhang, Xichun Hu, Wentao Yang, Jian Zhang
Journal: Journal of Clinical Oncology (2023)

1021 Background: Trastuzumab deruxtecan (T-DXd) was recently approved to treat unresectable/metastatic HER2-low breast cancer. However, patients whose primary tumor is HER2-0 but recurrent/metastatic lesion is HER2-low will lose therapeutic opportunities for T-DXd if a rebiopsy is not performed. In this study, with the largest sample size to date, we aimed to investigate the prevalence of HER2 status conversion. Moreover, it remains debated whether HER2-0 and HER2-low tumors have different prognoses, probably because previous studies did not assess HER2 status entirely based on recurrent/metastatic lesions. Our study aimed to fill this gap. Methods: We included 1299 patients with available HER2 status on both primary tumors and recurrent/metastatic lesions at Fudan University Shanghai Cancer Center and West China Hospital. Results: A total of 370 (28.5%) patients experienced HER2 status conversion throughout disease recurrence. 144 (31.7%) HER2-0 tumors converted to HER2-low. Inter-metastases heterogeneity of HER2 status was also observed. Compared to HER2-low tumors, HER2-0 tumors showed a higher TP53 mutation rate in the ER-positive subgroup, and a lower PIK3CA mutation rate in the ER-negative subgroup. Patients with tumors converting from HER2-0 to HER2-low had a longer overall survival (HR = 0.59, adjusted P = 0.033) than those with consistent HER2-0 status in the ER-negative subgroup. By combining four risk factors (ER status, Ki67 index, biopsy site, and disease-free interval), we established the first prediction tool to estimate the probability of HER2 status conversion from HER2-0 to HER2-low/positive. Conclusions: HER2 status was unstable during the disease course. Our prediction tool could help to screen out patients with a high probability of HER2 status conversion. Our results support that HER2-0 and HER2-low recurrent/metastatic tumors have different genomic features and prognoses.